Targeting TP53-Y220C mutant acute myeloid leukemia (AML)

TP53-Y220C is a recurrent hotspot mutation observed predominantly in acute myeloid leukemia (AML)/myelodysplastic syndromes among hematological malignancies. It is associated with poor outcome. PC14586 (rezatapopt), a small molecule that fills the structural pocket in the TP53-Y220C mutant protein and restores wild-type (WT) TP53 conformation has not been investigated in TP53-Y220C mutant AML. We here demonstrate that PC14586 stabilizes WT-p53 conformation and activates p53 targets but surprisingly with limited apoptosis induction in TP53-Y220C AML cell lines. To understand why activation of p53 with MDM2 inhibitor nutlin-3a sufficiently induces apoptosis in TP53-WT AML, while with PC14586 exerted limited apoptotic activity in isogenic TP53-Y220C cells, we investigated the transcriptional and transcription-independent activities of PC14585-reactived TP53.